Association of the polymorphisms rs179008 (TLR7), rs2004640 (IRF5), rs1800795 (IL-6) and rs2280788 (CCL5) with systemic lupus erythematosus in women of Mayan ethnicity from Yucatan.

Introduction: IFN-α is the main cytokine in SLE, and single nucleotide polymorphisms (SNP) in different genes could induce it. Aim: To determine the association of rs2004640 (IRF5), rs179008 (TLR7), rs1800795 (IL-6) and rs2280788 (CCL5) with SLE in Mexican women with Mayan ethnicity. Methods: DNA and RNA were isolated from the peripheral blood of 110 patients and 200 healthy control subjects. SNP genotyping and gene expression analysis of IRF5, TLR7, IL-6 and IFN-α were determined by real-time PCR and analyzed with SNP Stat, Stata 10.1 and Graph Pad Prism v5. Results: rs2004640, rs179008, and rs1800795 in both groups were according to Hardy-Weinberg equilibrium. Risk alleles rs179008T and rs2004640T frequencies were higher in controls (p = 0.015 and p = 0.028, respectively), whereas rs179008A frequency was higher in patients (p = 0.015). Allelic combination AGT frequency was higher in patients (p = 0.001). IL-6 rs1800795C > G and CCL5 rs2280788G > C frequencies did not show significant differences (p > 0.05), being rs2280788G (CCL5) monomorphic in controls. SLE patients showed higher TLR7, IRF5, IL6, and IFN-α mRNA levels. IRF5 expression was higher in SLE patients homozygous for rs2004640T (IRF5). Conclusion: This work showed the contribution of TLR7 and IRF5 in SLE pathogenesis in Mayan females from Yucatan.

L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by pathogenic variants in the L2HGDH gene which encodes mitochondrial 2-hydroxyglutarate dehydrogenase. Here, we report a case of L2HGA in a Mexican-Mayan patient with a homozygous mutation at L2HGDH gene and clinical response to vitamin supplements and levocarnitine. Case report: A 17-year-old, right-handed female patient with long-term history of seizures, developmental delay and ataxia was referred to a movement disorders specialist for the evaluation of tremor. Her brain MRI showed typical findings of L2HGA. The diagnosis was corroborated with elevated levels of 2-hydroxyglutaric acid in urine and genetic test which revealed a homozygous genetic known variant c.569C>T in exon 5 of L2HGDH gene. She was treated with levocarnitine and vitamin supplements, showing improvement in tremor and gait. Discussion: To our knowledge this is the first report of a Mexican patient with L2HGA. This case adds information about a rare condition in a different ethnic group and supports the findings of other authors which encountered symptomatic improvement with the use of flavin adenine dinucleotide (and its precursor riboflavin), and levocarnitine. Highlights: We report the first case of Mexican-Mayan patient with L2HGA showing a missense homozygous mutation in L2HGDH gene, and improvement of symptoms with vitamin supplements and levocarnitine.

Copy Number Variation and Frequency of rs179008 in TLR7 Gene Associated with Systemic Lupus Erythematosus in Two Mexican Populations.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which genetic factors play a role in the susceptibility to develop it. Genes related to the synthesis of interferons such as TLR7 and genetics factors such as single nucleotide polymorphisms (SNPs) or copies number variation (CNV) in the gene have been involved with the development of the disease. The genetic differences between the populations contribute to the complexity of LES. Mexico has a mestizo population with a genetic load of at least three origins: Amerindian, Caucasian, and African. The mestizo of Yucatán is the only group whose contribution Amerindian is mainly Mayan, geographically distant from other Mexican Amerindians. We analyzed the CNV and the frequency of SNP rs179008 of the TLR7 as genetic risk factors in developing the disease in patients from Yucatán and Central Mexico. Results show that 14% of the cases of the Yucatecan population showed significantly >2 CNV and a higher risk of developing the disease (OR: 34.364), concerning 4% of those coming from Central Mexico (OR: 10.855). T allele and the A/T and T/T risk genotypes of rs179008 were more frequent in patients of Central Mexico than in those of Yucatán (50% vs. 30%, 93% vs. 30%, 4% vs. 1%), and association with susceptibility to develop SLE was observed (OR: 1.5 vs. 0.58, 9.54 vs. 0.66, 12 vs. 0.14). Data support the genetic differences between and within Mexican mestizo populations and the role of the TLR7 in the pathogenesis of SLE.

Genetic variants of PON1, GSTM1, GSTT1, and locus 9p21.3, and the risk for premature coronary artery disease in Yucatan, Mexico.

OBJECTIVE: Genetic variants of PON1, rs70587, rs662, rs854560, GSTM1, and GSTT1 and two single nucleotide polymorphisms (SNP) at 9p21.3 locus, rs1333049, and rs2383207; were evaluated in association with the risk for premature coronary artery disease (CAD) in a population of Yucatan, Mexico. These genes are involved in the inactivation of pro-oxidants and pro-inflammatory mediators, lipid and xenobiotic metabolism, detoxification of reactive oxygen species, and regulation of cellular proliferation playing key roles in the pathogenesis of atherosclerosis. METHODS: We conducted a matched case-control study with 98 CAD cases and 101 healthy controls. Genotyping of PON1 and 9p21.2 SNP was performed by real time-PCR and for GSTM1 and GSTT1 with multiplex-PCR. Odds ratios (OR) were calculated to estimate association and generalized multifactor dimensionality reduction (GMDR) algorithm to identify gene-gene and gene-environment interactions. RESULTS: The distribution of all allele/genotype frequencies in controls was within Hardy-Weinberg expectations (p > .05) except for GSTM1. The allele/genotype frequencies of the GSTT1 null were significantly higher in CAD cases than in controls, suggesting association with higher risk for developing CAD. The other SNPs did not show any significant independent association with premature CAD. GMDR revealed a significant interaction between GSTT1 and LL55 genotype. Likewise, the body mass index (BMI) and smoking also showed an interaction with GSTT1. CONCLUSION: The GSTT1 null allele/genotype is associated with an increased risk of developing premature CAD, the effect of which is not modified by cardiovascular risk factors in the population of Yucatan.

High expression levels of circulating microRNA-122 and microRNA-222 are associated with obesity in children with Mayan ethnicity.

OBJECTIVES: High expression levels (HELs) of microRNA-122 (miR-122) or microRNA-222 (miR-222) have been associated with insulin resistance (IR), which leads to the development of obesity. The association between HELs of circulating miR-122 and miR-222 and the risk of obesity was evaluated in Mexican school-aged children, where childhood obesity is the primary cause of morbidity. METHODS: Anthropometric data, biochemical parameters, and caloric intake were obtained in 50 children with obesity and 49 children with normal weight. The expression of circulating miR-122 and miR-222 was measured by quantitative real-time polymerase chain reaction amplification. Data were analyzed using Student t test, Pearson correlation coefficient, associations with chi-square, and multiple linear and logistic regressions with SPSS software v.23. RESULTS: The mean relative expression for miR-122 and miR-222 was 0.33 and 5.65, respectively, for children with obesity and 0.22 and 3.16, respectively, for children with normal weight. The expression of miR-122 and miR-222 was 1.47 and 1.78-fold higher, respectively, in children with obesity (P = 0.001 and P = 0.025). HELs of both miR-122 and miR-222 were associated with body mass index (BMI), waist to height ratio (WHR), fat percentage, serum high-density lipid levels, triglycerides (TGs), and metabolic index (MI) (P < .001). CONCLUSIONS: The HELs of circulating miR-122 conferred a 3.85-fold increase in the risk for obesity, whereas the HELs of both miR-122 and miR-222 conferred a 3.11-fold increase in the risk for obesity, which were also associated with higher anthropometric or biochemical parameters, such as BMI, WHR, fat percentage, serum high-density lipid levels, TGs, and MI, in Mayan children.

Correction to: A four-step mutation at D22S1045 in one complex paternity case when the brother of the alleged father hypothesis is evaluated.

This article was published online with an error. Given names and family names of the authors were interchanged. The correct author names are presented above. The original article has been corrected.

A four-step mutation at D22S1045 in one complex paternity case when the brother of the alleged father hypothesis is evaluated.

We report one complex paternity case presenting a presumable paternal four-step STR mutation between the alleged father (AF) and child; the complexity of the case required the AF-brother hypothesis to be discarded without including this DNA sample. A total of 23 autosomal STR loci included in the Powerplex Fusion® and Globalfiler™ kits confirmed one isolated mismatch for D22S1045 between the AF (17/17) and the male child (13/15) in the presence of the mother (15/15). In this case, the STR structure and father's age do not seem to have contributed to promote the observed multistep mutation. The Paternity Index (PI) based on 23 autosomal STRs did not favor the AF paternity over the AF-brother hypothesis based on a flat prior (PI = 0.1217; W = 10.85%). For that reason, we included 38 autosomal human identification (HID) insertions-deletions (indels) and 20 retrotransposon insertion polymorphisms (RIPs) contained in the InnoTyper® 21 kit. Although these biallelic markers favored the AF paternity rather than the AF-brother hypothesis (LR = 110.3; W = 99.1%), the global PI based on 81 autosomal markers supported moderately the AF paternity hypothesis (LR = 13.4; W = 93.1%). The application of different mutation models showed a consistent support to the AF paternity hypothesis (PI = 93.1-99.95%), which could be useful for interpretation in these multistep STR mutation cases. In brief, we showed the impact of a four-step mutation at D22S1045 to obtain definitive paternity conclusions, particularly under a complex scenario when the AF-brother hypothesis is assessed. Forensic genomics arises as the next option for similar complex paternity cases.

Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school-aged children with obesity/overweight and with normal weight.

OBJECTIVES: Genetic variation of the fat mass and obesity associated gene (FTO) has been identified as a risk factor for obesity and obesity traits. Distribution of FTO single nutleotide polymorphisms (SNPs) rs1421085T>C, rs9939609T>A, rs8057044G>A and copy number variation (CNV) was evaluated in association with childhood obesity or overweight status in children with Mayan ethnicity. METHODS: We included 318 school-aged children with obesity or overweight status (body mass index [BMI]: >85th percentile) and 303 children with normal weight (BMI: 15th-85th percentile). Genotyping was performed using real-time polymerase chain reaction (RT-PCR) with TaqMan probes. The cross-sectional study was carried out using univariate and multivariate logistic regression models adjusted for gender. RESULTS: FTO-SNP rs1421085 showed significant differences between children with obesity and children with normal weight for the heterozygous genotype (P = 0.003) and for allele frequencies (P = 0.023). Adjusting by gender, significant differences were found in frequencies of the hetezygous genotype of SNPs rs9939609 (P = 0.023) and rs1421085 (P = 0.003) as well as in allele frequencies (P = 0.042 and P = 0.013, respectively) between girls with obesity and girls without obesity. In contrast, SNP rs8057044 was significantly different only between heterozygous overweight versus normal weight boys (P = 0.035) and for the allele frequency of rs8057044 (P = 0.021). The mean relative CNV was significantly higher in male overweight children than in boys with normal weight (P = 0.000). CONCLUSIONS: The FTO SNP rs1421085 is a genetic factor associated with obesity in Mayan school-aged children. FTO SNPs rs1421085 and rs9939609 affect genetic susceptibility for obesity only in girls, whereas, SNP rs8057044 and CNV are associated with overweight status only in boys.

Determinación de mutaciones (del E746-A750 exón 19 y L858R exón 21) en el gen receptor del factor de crecimiento epidérmico (EGFR) en muestras de suero y biopsia de carcinoma pulmonar no microcítico (CPNM) / Determination of mutations (del E746-A750 exon 19 and L858R exon 21) in the epidermal growth factor receptor (EGFR) gene in serum samples and in biopsys of non-microcytic lung carcinoma (NMLC)

Resumen Introducción Las mutaciones, del E746-A750 exón 19 y L858R exón 21 del gen EGFR en células tumorales de CPNM representan biomarcadores de respuesta a fármacos inhibidores de tirosina cinasa (ITK). Pacientes con tumores positivos a mutaciones EGFR muestran mejor respuesta y mayor sobrevivencia. Estas mutaciones ocupan el 90% de las mutaciones en cáncer de pulmón. Objetivo Evaluar la frecuencia de las mutaciones del E746-A750 exón 19 y L858R exón 21 del EGFR en muestras de biopsia de CPNM y en muestras de suero de población abierta de Yucatán. Material y métodos Se seleccionaron 19 muestras de biopsia de CNPM tipo adeconocarcinoma y 101 sueros de sujetos sanos. Las mutaciones del E746-A750 y L858R en EGFR se determinaron mediante amplificación por PCR oligo-alelo específica (PCR-ASO). Se calcularon las frecuencias genotípicas y alélicas y su distribución según Hardy Weinberg, utilizando la plataforma SNPstats. Resultados En muestras de suero se determinó el genotipo homocigoto (1/1) en 26.58%, 73.42% el heterocigoto (1/0) y ausencia del genotipo mutante con deleción (0/0) para del E746-A750; en tanto que, para L858R, 21.78% resultó homocigoto (TT), 54.46% heterocigoto (T/G) y 23.76% mutantes GG. En las biopsias, el heterocigoto fue más frecuente en ambas mutaciones 63.16% y 73.68% para del E746-A750 y L858R, respectivamente. Conclusión. La frecuencia de las mutaciones del gen EGFR en las muestras de sueros fue de 36.71% para la deleción del E746-A750 en exón 19 y 50.99% para L858R en exón 21. La distribución de las mutaciones en muestras de biopsia CPNM resultó en 42.11% para cada mutación estudiada.

Abstract Introduction EGFR mutations, del E746-A750 in exon 19 and L858R in exon 21 in tumor cells of NMLC represent biomarkers of response to tyrosine kinase inhibitors (TKI) therapy. Patients with tumors positive for EGFR mutations show better response and greater survival. These mutations occupy 90% of mutations in lung cancer. Objective To evaluate the frequency of mutations del E746-A750-exon 19 and L858R-exon 21 of EGFR gene in NMLC biopsy samples and in serum samples of the general population from Yucatán. Material and methods 19 NMLC biopsy samples of adenocarcinoma type and 101 serum samples from healthy subjects were selected. EGFR mutations del E746-A750 and L858R were determined by allele-specific PCR amplification (PCR-ASO). The genotypic and allelic frequencies; and their distribution according to Hardy Weinberg expectations were calculated using the SNPstats software. Results For serum, EGFR del E746-A750 mutation, homozygous genotype (1/1) was present in 26.58%, heterozygote (1/0) in 73.42% and absence of mutant genotype with deletion (0/0); whereas for L858R mutation, 21.78% were homozygous (TT), 54.46% heterozygous (T/G) and 23.76% GG mutants. For the NMLC biopsies, the heterozygote was the most frequent genotype for both mutations, 63.16% and 73.68% for del E746-A750 and L858R, respectively. Conclusion The frequency of mutations of EGFR gene in serum samples was 36.71% for deletion delE746-A750 in exon 19 and 50.99% for L858R in exon 21. Distribution of mutations in biopsy samples NMLC resulted in 42.11% for each EGFR mutation.

The Paraoxonase 1 Gene c.-108C>T SNP in the Promoter Is Associated with Risk for Glioma in Mexican Patients, but Not the p.L55M or p.Q192R Polymorphisms in the Coding Region.

AIM: To evaluate the association of the paraoxonase 1 (PON1) gene polymorphisms c.-108C>T, p.L55M, and p.Q192R with the risk of glioma in Southeast Mexico. Decreased PON1 activity caused by polymorphisms has been observed in gliomas, thus supporting the theory that PON1 is involved in tumorigenesis in the brain. METHODS: Sixty-seven glioma patients and 58 control individuals were included. Three PON1 polymorphisms were genotyped by real-time PCR allelic discrimination using TaqMan probes: c.-108C>T in the promoter region, p.Q192R and p.L55M, both of which were in the coding region. Allele, genotype, and haplotype frequencies were assessed in cases and controls to test for statistical associations (STATA 10.2 package). RESULTS: Significant differences were found for the PON1 c.-108C>T polymorphism between the cases and controls. Compared to the controls the cases were more likely to be CT heterozygous (p = 0.002) or TT homozygous (p = 0.036); similarly cases were more likely to possess a T allele (p = 0.032). In contrast, the p.L55M and p.Q192R polymorphisms did not show significant differences between the glioma cases and controls (p > 0.05). CONCLUSION: The PON1 c.-108C>T polymorphism in the promoter region is associated with genetic risk for glioma. Conversely, p.L55M and p.Q192R polymorphisms in the coding region do not seem to have an influence in this population.

[G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico]. / Polimorfismos G894T del gen NOS3 y G1958A del gen MTHFD1 y riesgo de cardiopatía isquémica en Yucatán, México.

INTRODUCTION AND OBJECTIVES: Cardiovascular medicine is focused on the search for genetic risk markers with predictive and/or prognostic value. Among the genetic variants of interest are G894T endothelial nitric oxide synthase and G1958A methylenetetrahydrofolate dehydrogenase1 gene polymorphisms. The aim of this study was to determine the possible association between these polymorphisms and ischemic heart disease in patients from Southern of Mexico (Yucatán). METHODS: Case-control study matched by age, sex and origin was designed. We studied 98 patients with coronary disease and 101 controls. Participants were evaluated for the usual risk factors. The polymorphisms were identified using the polymerase chain reaction/restriction fragment length polymorphism analysis. Informed consent was obtained from all participants. RESULTS: The G894T and G1958A polymorphisms were not associated with ischemic heart disease, however, the TT genotype (G894T) was associated with the angina (OR=10.2; 95%CI, 1.51-68.8; p=0.025). The genotype GT (G894T) was the most frequent in patients with family history of coronary artery disease. Multiple logistic regression analysis identified smoking (OR=5.21; 95%CI, 2.1-12.9; p=0.000), hypertension (OR=3.54; 95%CI, 1.47-8.56; p=0.005) and obesity (OR=1.16; 95%CI, 1.1-1.27; p=0.001) as risk factors predicting the ischemic heart disease. CONCLUSIONS: The G894T and G1958A polymorphisms showed not association with ischemic heart disease. However, homozygosis for the 894T allele (NOS3) confers at risk to develop angina on Yucatán.

VDR polymorphisms are associated with bone mineral density in post-menopausal Mayan-Mestizo women.

BACKGROUND: Osteoporosis is characterized by low bone mineral density (BMD), which is determined by an interaction of genetic, metabolic and environmental factors. AIM: To analyse the association between two polymorphisms of VDR as well as their haplotypes with BMD in post-menopausal Maya-Mestizo women. SUBJECTS AND METHODS: This study comprised 600 post-menopausal Maya-Mestizo women. A structured questionnaire for risk factors was applied and BMD was assessed at the lumbar spine (LS) and total hip (TH) by dual-energy X-ray absorptiometry. DNA was extracted from blood leukocytes. Two single-nucleotide polymorphisms of VDR (rs731236 and rs2228570) were studied using real-time PCR allelic discrimination for genotyping. Differences between the means of the BMDs according to the genotype were analysed with covariance. Haplotype analysis was conducted. RESULTS: TT genotype of rs731236 of VDR had higher BMD at total hip and femoral neck (FN), and one haplotype formed by the two polymorphisms was associated with only TH-BMD variations. This difference was statistically significant after adjustment for confounders. The genotype of rs2228570 of VDR analysis showed no significant differences with BMD variations. CONCLUSION: The results showed that the TT genotype of rs731236 of VDR and one haplotype formed by rs731236 and rs2228570 polymorphisms were associated with higher BMD at TH and FN.

Copy Number Variation of TLR-7 Gene and its Association with the Development of Systemic Lupus Erythematosus in Female Patients from Yucatan Mexico.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies against self-antigens, which occurs most often in women between 15 and 40 years of age. The innate immunity is involved in the pathogenesis of SLE through TLR- 7. Genetic factors such as copy number variation (CNV) of target genes may contribute to disease development, but this possible risk has not yet been studied in SLE patients from Yucatan, Mexico. The CNV of TLR-7 gene was determined by quantitative polymerase chain reaction assay using TaqMan probes in 80 SLE women and 150 control subjects. The results showed that 10% of SLE patients exhibited more than two copies of TLR-7 gene, whereas no mRNA overexpression was detected. These data suggested that increased CNV of the TLR-7 gene in Yucatan SLE women can be a risk factor for this disease.

Metabolic abnormalities and polymorphisms of the vitamin D receptor (VDR) and ZNF365 genes in children with urolithiasis.

Composition of urinary stones in children from Yucatán, México, is calcium and uric acid. Polymorphisms in VDR and ZNF365 genes have been associated to calcium and uric acid lithiasis, respectively. We evaluated the association of polymorphisms TaqI and FokI of VDR gene and Ala62Thr of ZNF365 gene with the metabolic disorders (MD) in children with urolithiasis (UL). We included 109 children with UL. Creatinine, calcium, phosphorus, magnesium, uric acid, oxalates and citrates were measured in fresh urine. Urinary indices were calculated for determining the MD. VDR and ZNF365 polymorphisms were determined by PCR-RFLP. Genotype frequencies were compared with the frequency of MD and with the averages of excretion of the analytes, using the statistical package STATA 11.0. The most frequent MD were hypocitraturia (35.8 %) and hyperuricosuria (22.9 %). The comparison of genotype frequencies with the frequency of MD did not show significant differences (p > 0.05). The comparison of the urinary excretion averages of analytes with respect to the genotype showed that GG homozygotes have higher concentrations of uric acid and citrate than AG heterozygotes (p = 0.03), and that fF heterozygotes have lower concentrations of citrate (p = 0.009). Hypocitraturia and hyperuricosuria were the most common metabolic disorders. The frequency of MD is not associated with polymorphisms. However, in children with urolithiasis of Yucatan, GG homozygotes excrete higher concentrations of uric acid and citrates, and fF heterozygotes have lower concentrations of citrates.

MTHFR/p53 polymorphisms as genetic factors for cervical intraepithelial neoplasia and cervical cancer in HPV-infected Mexican women.

We performed a case-control association study to evaluate the association between common polymorphisms in MTHFR (C677T and A1298C) and the Arg72Pro polymorphism in the p53 gene and the risk for cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC) in Mexican HPV-infected women. We included 131 women with diagnosis of CIN grade I-II and 78 with CIN III or ICC; as controls we also included 274 women with normal Pap smear and negative HPV test. Genotyping for MTHFR and p53 polymorphisms was performed by PCR-RFPLs. HPV was tested by Hybrid Capture II. Odds ratios and 95% confidence intervals were estimated. Genotype frequencies for the 3 studied polymorphisms were distributed according to the Hardy-Weinberg equilibrium. The A1298C-MTHFR polymorphism showed significant differences for the heterozygous AC genotype and the C allele, whereas the AA genotype and A allele resulted to be genetic risk factors for CIN or ICC (p<0.03). The Arg72Pro-p53 polymorphism showed for the genotypes Arg/Pro and Pro/Pro, and for the Pro allele, a significant association only to the risk for CIN (p<0.03). The MTHFR/p53 interaction showed that the genotype combinations AA/ArgArg and AA/ArgPro were associated, respectively, to the risk of ICC and CIN (p<0.05). This study suggests that the A1298C-MTHFR polymorphism contributes to the genetic risk for both CIN and ICC, whereas the Arg72Pro-p53 polymorphism only contributes to the risk for CIN. The MTHFR/p53 genetic combinations AA/ArgArg and AA/ArgPro are associated genetic risk factors for ICC and CIN in Mexican HPV-infected women.

Polymorphism of LRP5, but not of TNFRSF11B, is associated with a decrease in bone mineral density in postmenopausal Maya-Mestizo women.

OBJECTIVE: Osteoporosis is a complex disease characterized principally by low bone mineral density (BMD), which is determined by an interaction of genetic, metabolic, and environmental factors. The aim of this study was to analyze the possible association among one polymorphism of LRP5 and three polymorphisms of TNFRSF11B as well as their haplotypes with BMD variations in Maya-Mestizo postmenopausal women. METHODS: We studied 583 postmenopausal women of Maya-Mestizo ethnic origin. A structured questionnaire for risk factors was applied and BMD was measured in lumbar spine (LS), total hip (TH), and femoral neck (FN) by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. One single-nucleotide polymorphism of LRP5 (rs3736228, p.A1330V) and three of TNFRSF11B (rs4355801, rs2073618, and rs6993813) were studied using real-time PCR allelic discrimination for genotyping. Differences between the means of the BMDs according to the genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r(2), and haplotype analysis of TNFRSF11B was conducted. RESULTS: The Val genotype of the rs3736228 (p.A1330V) of LRP5 was significantly associated with BMD variations at the LS, TH, and FN. None of the three polymorphisms of TNFRSF11B was associated with BMD variations. CONCLUSIONS: Our results show that p.A1330V was significantly associated with BMD variations at all three skeletal sites analyzed; the Val allele and the Val/Val genotype were those most frequently found in our population.

Paraoxonase 1 polymorphisms and haplotypes and the risk for having offspring affected with spina bifida in Southeast Mexico.

BACKGROUND: Spina bifida (SB) is a common congenital malformation in Southeast Mexico. Parents of children with SB reside in areas with frequent pesticide spraying or have agriculture activities, suggesting potential exposure to pesticides. Paraoxonase 1 (PON1) is the responsible enzyme for deactivation of organophosphates (OP) in the central nervous system. Polymorphisms of PON1 genes influence the catalytic activity and plasma protein level of the enzyme, therefore, genotypic characterization of PON1 gene represents a potential predictor for susceptibility to OP-related effects. METHODS: The frequency of PON1 haplotypes and polymorphisms (-108CT, L55M, and Q192R) were determined in this study. A case-control study was performed to evaluate the risk for having offspring affected by SB in 152 cases and 160 control parents. Polymorphisms were determined by PCR amplification and restriction fragment length polymorphism and Real Time-PCR. Odds ratios and confidence interval 95% were estimated. RESULTS: Genotype frequencies for the three PON1 polymorphisms were distributed according to Hardy-Weinberg expectations (p > 0.05) and were significantly different between cases and controls (p < 0.05). The heterozygous CT genotype of -108CT polymorphism, the RR genotype of Q192R polymorphism, both LM and MM genotypes of L55M polymorphism, and the haplotypes 221 and 222 (for -108CT, L55M, and Q192R) were associated with the risk for having a child affected by SB (p < 0.02). The heterozygous -108CT genotype was associated only maternally, whereas the heterozygous L55M genotype was relevant only in the fathers. The RR homozygous genotype was relevant both in mothers and fathers, suggesting the importance of this substrate-specific polymorphism. CONCLUSION: Results suggest that PON1 polymorphisms are relevant risk factors for having offspring affected with SB in this population from Southeast Mexico.

A1298C polymorphism of the MTHFR gene and neural tube defects in the state of Yucatan, Mexico.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) of the folate metabolism pathway is a candidate gene for neural tube defects (NTDs). Frequency of the second common polymorphism, A1298C, in the MTHFR gene is not well known in Mexico. Conflicting results exist regarding the association of A1298C-MTHFR with NTDs. One explanation for this controversy might be that alleles are differently distributed among various populations. The aim of the study was to determine the frequency of the A1298C-MTHFR polymorphism and its association with NTDs in a population of Yucatan, Mexico. METHODS: Genotyping was performed by use of polymerase chain reaction with restriction fragment length polymorphisms using MbOII endonuclease (PCR-RFLPs MbOII). Allele and genotype frequencies were compared between cases with NTDs, their mothers and fathers with matched controls based on an association analysis using EpiInfo software. RESULTS: A1298C genotypes were distributed according to Hardy-Weinberg expectations for all studied groups. Frequencies of allele C and heterozygous AC genotype were significantly higher in males (p = .006 and p = .011, respectively) in control group. Significant differences were not observed between cases and controls, except in mothers of NTD cases compared with mothers of healthy offspring for both allele C and heterozygous AC genotype (p = .009 and p = .01, respectively). CONCLUSIONS: The polymorphism A1298C-MTHFR is not associated with NTDs, except for mothers, suggesting only a maternal association with having NTD-affected offspring in the Yucatan population. The frequency of allele C in the control population was 10%, which is significantly lower than in other reported control populations worldwide (p < .01).